Fish oils (FO) and omega-3 fatty acids (w-3 FAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are some of the most prevalent natural dietary supplements used in the U.S., with an estimated retail market size as high as 30 billion dollars annually. Among a variety of health benefits, it has been demonstrated that the consumption of w-3 FAs lows the triglyceride levels. Nevertheless, the underlying mechanisms are not well established and shadowed by inconclusive and conflicting results shown in the literature. Furan fatty acids (FuFAs), a class of minor natural components, were found present in FO and w-3 FA prescription drugs (~3% in Lovaza). Preliminary data has shown that FuFAs potently inhibit acetyl-CoA carboxylate (ACC), a known pharmacological target that regulates lipogenesis and lipid metabolism. We propose that FuFAs are responsible for the hypotriglyceridemic effects observed with the use FO and w-3 FA products. Furanica has the patented synthetic approach to produce an ample supply of high purity FuFAs, the lack of which has hampered its research and development to date. The versatile synthetic pathway will deliver a series of naturally occurring FuFAs as well as the isotopically-labeled analogues for accurate quantification and animal studies. SA1: Improve FuFA bioanalytical tools and measure FuFA levels in commercial fish oil and w-3 FA products. The inconsistent results associated with w-3 FAs might be due in part to differences in FuFA levels among various sources. Bioanalytical tools will be developed using our FuFA standards and the isotopically- labeled analogues for the accurate measurement of FuFA levels in selected commercial products. SA2: Establish the oral bioavailability of FuFAs in a rodent model. Absolute oral bioavailability of FuFAs will be determined in a rodent model after oral gavage and IV administrations of 11D3 (one of the most common FuFAs). Plasma levels of 11D3 and its metabolite CMPF, along with their tissue distributions (e.g. liver and pancreas) will be monitored to elucidate the role of FuFA exposure and the formation of CMPF. SA3: Reveal the direct role of FuFA in lowering triglycerides in a high fat diet (HFD) mouse model. 11D3 administration in an established HFD intervention model will answer whether FuFAs dosed at levels present in w-3 FA products are responsible for the hypotriglyceridemic effects. Plasma and hepatic triglyceride levels at the end of the study will be determined and compared with those of the control, FuFA-free w-3 FAs, and CMPF. Oral glucose tolerance tests and insulin tolerance tests will also be performed to demonstrate the status of glucose handling at the end of the treatments. A successful outcome of this proposal will alter the current paradigm and allow for new dietary and pharmacological approaches to managing hypertriglyceridemia to be developed involving FuFAs.